Summary of Work: AIMS: As many as 50% of AIDS patients suffer from multiple nAIMS: As many as 50% of AIDS patients suffer from multiple neurological symptoms collectively termed as AIDS- related dementia. The neurotoxicity of the HIV-1 envelope protein gp120 has been implicated in the neuropathology of AIDS. Results from several lines of research indicate that gp120 causes the death of neurons through the activation of microglia which release neurotoxic substances, such as proinflammatory cytokines and nitric oxide (NO). The purpose of this project is to study the signal transduction pathways mediating the gp120-induced expression of immune modulators following the activation of microglia. ACCOMPLISHMENTS: Glial cells in the brain are required for the HIV envelope protein gp120-induced neuronal cell injury. However, the signal transduction pathways for the gp120-induced neurotoxic effects are not well understood. Because the immediate-early genes c-fos and c-jun are induced rapidly in the brain by a variety of neurotoxins and are closely associated with neuronal cell death, we examined the effects of gp120 obtained from the HIV-1IIIB virus on the expression of c-fos and c-jun in mouse primary glial cell cultures with the semi- quantitative reverse transcription-polymerase chain reaction. A measurable increase in the mRNA for c-Fos or c-Jun was first detected 10 min after gp120 treatment. The highest amounts of the mRNA for c-Fos or c-Jun were seen at 60 min. The gp120- induced stimulation of the mRNA for c-Fos or c-Jun was inhibited by calyculin A, an inhibitor of protein phosphatase 1 (PP1) and 2A (PP2A). These results demonstrate that HIV-1IIIB gp120 stimulates the immediate-early genes c-fos and c-jun in brain glial cells, and that PP1 and/or PP2A may be implicated in the HIV-1IIIB gp120-induced signal transduction pathways. These results may provide insights into development of therapeutic interventions in the pathway(s) for the gp120-induced neurotoxicity.